Interaction of germline and somatic changes in PCa progression Abstract Recent successes in discovering germline variants associated with prostate cancer (PCa) risk is encouraging. However, whether these risk variants play role in PCa progression is unclear. Understanding factors associated with the progression of PCa will have a significant impact on management and treatment of the disease. We hypothesize that germline risk variants, combined with somatic genetic and epigenetic changes may increase the risk of prostate cancer progression. To test this hypothesis and to uncover the genetic and epigenetic markers of the complex mechanisms underlining the progression and poor clinical outcome of PCa, we present three specific aims with integrated and novel analytic approaches in this proposal. First, for the genomic regions where germline variants are associated with PCa risk, we will screen for potential germline CNVs, somatic DNA copy number changes and/or methylation modifications among 96 PCa patients who have developed progressed disease. Several novel global DNA copy number and methylation detection methods will be employed to examine DNA samples isolated from frozen tumor and normal prostate tissues. Secondly, we will test whether known germline PCa risk variants, when combined with somatic DNA changes and/or methylation modifications identified in Aim 1, are associated with increased risk for PCa progression in an existing and well-designed study population from Johns Hopkins Hospital, including 800 pairs of progressors and matched non-progressors. Finally, we will identify genes whose protein expression levels are associated with genetic and epigenetic alterations that are implicated in Aim 2. The results of this study may advance our understanding on the etiology of PCa progression and augment current methods to better predict which PCa patients are most likely to develop progressed disease at the time of diagnosis. The PCa patients with poor prognosis can receive intensive monitoring and treatment. PUBLIC HEALTH RELEVANCE: This proposal intends to identify interaction effects on prostate cancer (PCa) progression for several known germline (PCa) risk variants genetic and somatic genetic and epigenetic changes identified in our study, using several global detection methods. The identified genes may advance our understanding on the etiology of PCa progression and augment current methods to better predict which PCa patients are most likely to develop progressed disease at the time of diagnosis. The PCa patients with poor prognosis can receive intensive monitoring and treatment.